using genetic markers in clinical practice david thomas advisor: merck clinical trial: gilead and...
TRANSCRIPT
![Page 1: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/1.jpg)
Using genetic markers in clinical practice
David Thomas
Advisor: MerckClinical trial: Gilead and Merck
![Page 2: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/2.jpg)
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
![Page 3: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/3.jpg)
Recovery Persistence
![Page 4: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/4.jpg)
Ge, Nature, 2009; Thomas, Nature 2009; Rauch Gastroenterology 2010
Seven SNPs within a 17-kb region around IL28B gene are associated with HCV recovery
![Page 5: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/5.jpg)
Seven SNPs within a 17-kb region around IL28B gene are associated with HCV recovery
![Page 6: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/6.jpg)
Ge, Nature, 2009
C allele associated with PegIFN and RBV in IDEAL
![Page 7: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/7.jpg)
Clark Am J Gastro
IL28b genotyping helps predict SVR in Caucasians
![Page 8: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/8.jpg)
Clark Am J Gastro
IL28b genotyping helps predict SVR in African Americans
![Page 9: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/9.jpg)
Independent replication of the effect of genetic variation in SNPs near IL28B and
SVR
Ge et al Tanaka et al Suppiah et al Rauch et al
Race Americans: European; African; Hispanic
Japanese European; Australian
European
SNP rs8099917;1.72 x 10-26
rs8099917;2.68 x 10-32
rs8099917;9.25 x 10-9
rs8099917;5.7 x 10-8
rs1297860;1.37 x 10-28
Gene IL28B IL28B IL28B IL28B
Adjusted odds ratio of failure by rs8099917 carriage
5.6, Hispanic6.1, African7.3, Caucasian
12.1 1.98 5.2
Ge D, et al. Nature 2009;461:399-401. Tanaka Y, et al. Nat Genet 2009;41:1105-9. Suppiah V, et al. Nat Genet 2009;41:1100-4. Rauch A, et al. Gastroenterology 2010; Jan 7.
![Page 10: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/10.jpg)
Kinetics of HCV RNA decline differ early in IL28b haplotypes
Genotype 1 Caucasian patients
![Page 11: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/11.jpg)
IL28b haplotype predicts SVR in HIV/HCV coinfected patients
Rallon AIDS 2010 (Pineda CID 2010, Medrano CID 2010)
![Page 12: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/12.jpg)
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
![Page 13: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/13.jpg)
Mangia Gastro 2010
Effect of unfavorable IL28b genotype is less in Caucasian genotype 2/3 HCV infection
Genotype 2, N=213; Genotype 3, N=55
![Page 14: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/14.jpg)
Favorable IL28b genotype may be associated with relapse of genotype
3 HCV infection • 281 genotype
3, Scandinavian, >11wks Rx
• RVR, 14 wks peg/R no RVR, 24 wks
• Overall SVR 80%
• CC relapse:o 13/64 (20%)
14wko 7/43 (16%) 24
wk
Moghaddam Hepatology 2011
![Page 15: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/15.jpg)
Both donor and recipient IL28 status are important for outcome of IFN treatment after liver
transplant
Charlton Hepatology 2011
![Page 16: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/16.jpg)
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
![Page 17: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/17.jpg)
C allele associates with higher probability of spontaneous clearance of
HCV
Thomas Nature 2009; Grebely Hepatology 2010; Rauch Gastro 2010
![Page 18: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/18.jpg)
Persons with acute hepatitis C and unfavorable IL28b genotype should be
treated sooner • With genotype 1, interferon alfa
sensitivity diminishes with time from acute infection
• Interferon alfa sensitivity diminishes most with genotype 1
• Prioritize early treatment for T allele• May not be case for HIV/HCV
coinfected1
1Nattermann JID 2011
![Page 19: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/19.jpg)
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
![Page 20: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/20.jpg)
EOT and SVR according to rs12979860 genotype
72 patients Telaprevir/PegIFN/RBV for total duration of 12 or 24 weeks
Akuta N et al. Hepatology 2010
![Page 21: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/21.jpg)
SPRINT-2 Treatment-Naïve Patients
Stopping Rule
Weeks 12 24 28 48 72
Follow-up24 wks
TW 8-24 Undetectable
Follow-up
24 wks
TW 8-24 Detectable
Follow-up24 wks
8
Placebo + P/R
44 wks
P/R4 wks
Follow-up24 wks
BOC + P/R
24 wks
P/R4 wks
Follow-up44 wks
Placebo + P/R 20 wks
BOC + P/R
44 wks
P/R4 wks
Decision point for long vs. short therapy
Arm 1PR48
Control
Arm 2BOCRGT
Arm 3BOC/PR48
Lead-in
![Page 22: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/22.jpg)
RESPOND-2 Previous Treatment Failure
Stopping Rule
Weeks 12 24 48 72
Placebo + P/R
44 wks
P/R4 wks
Follow-up24 wks
Arm 1PR48
Control
TW 8 Undetectable
BOC + P/R
32 wks
P/R4 wks
Follow-up36 wks
Placebo + P/R12 wks
Follow-up
24 wks
TW 8 Detectable
Arm 2BOCRGT
BOC + P/R
44 wks
P/R4 wks
Follow-up24 wks
Arm 3BOC/PR48
8 36
Decision point for long vs. short therapy
Lead-in
![Page 23: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/23.jpg)
consented to testing and who received ≥1 dose BOC or placebo (63%)
Distribution of IL-28B Polymorphisms
RESPOND 266%
(259/394)
SPRINT 262%
(653/1048)
TT (15%)CC
(24%)
CT (61%)
TT (19%)
CC (30%)
CT (51%)
SPRINT 2 team: Poordad EASL 2011
![Page 24: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/24.jpg)
Improvement in SVR in naïve patients with boceprevir is greater
with T allele
SPRINT 2 team: Poordad EASL 2011
![Page 25: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/25.jpg)
Improvement in SVR in retreated patients with boceprevir is greater
with T allele
RESPOND 2 team: Poordad EASL 2011
![Page 26: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/26.jpg)
IL-28B CC polymorphism is a strong predictor of TW8
response*
% Patients with undetectable HCV-RNA by TW8
CC
CT + TT
SPRINT-2 RESPOND-2
*Decision point for short vs. long treatment duration with RGT
4150
80156
118132
158304
![Page 27: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/27.jpg)
Early Interferon Response (Lead-In) Further Defines Likelihood of Success For Non-CC
Patients
02
23
24
5675
83102
5872
127 19
512045
37117
83111
109133
120 6
251025
1326
2328
2634
CC CT TT≥ ≥ ≥
SPRINT-2 and RESPOND-2 combined
![Page 28: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/28.jpg)
Design of the ADVANCE Study of Telaprevir in Treatment Naïve HCV
genotype 1 Patients
![Page 29: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/29.jpg)
Differences between ADVANCE cohort and those typed
![Page 30: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/30.jpg)
Improvement in SVR in Caucasian naive patients with telaprevir is greater with T
allele
ADVANCE TEAM, Jacobson EASL 2011
![Page 31: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/31.jpg)
REALIZE (retreatment) Study Design
484 160 128
Weeks
72
T12/PR48Peg-IFN + RBV
TVR + Peg-IFN + RBV
Pbo + Peg-IFN +
RBV n=212 Follow-up
SVR assessment
TVR + Peg-IFN + RBV
Peg-IFN + RBVLead-in
T12/PR48
n=210Follow-up
Pbo + Peg-IFN +
RBV
Pbo/PR48 Pbo +
Peg-IFN + RBV Peg-IFN + RBV
n=105Follow-up
![Page 32: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/32.jpg)
SVR Rates by IL28B Genotype and Prior
ResponsePrior
relapsers
Patients achieving SVR (%)
Prior partial
responders
Prior null responders
CC CT TT CC CT TT CC CT TT
Pooled T12/PR48 (n=209)Pbo/PR48 (n=52)
Pooled T12/PR48 (n=79)Pbo/PR48 (n=20)
Pooled T12/PR48 (n=134)Pbo/PR48 (n=33)
51/58 4/12100/117 6/30 29/34 3/10 5/8 1/5 33/57 2/10 10/14 0/5 4/10 27/92 1/18 10/32 1/15n/N=
n/a
Pol et al EASL 2011
![Page 33: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/33.jpg)
Viral Breakthrough Rates by IL28B Genotype and Prior Response
Viral breakthrough defined as confirmed HCV RNA increase >1 log10 from the lowest level during a considered treatment phase, or confirmed HCV RNA >100 IU/mL in patients who previously reached <25 IU/mL during the considered treatment phase
Patients with viral breakthrough (%)
Prior relapsers Prior partial responders
Prior null responders
CC CT TT CC CT TT CC CT TT
Pooled T12/PR48 (n=209)Pbo/PR48 (n=52)
Pooled T12/PR48 (n=79)Pbo/PR48 (n=20)
Pooled T12/PR48 (n=134)Pbo/PR48 (n=33)
1/58 0/12 2/117 4/30 0/34 0/10 1/8 1/5 9/57 1/10 1/14 0/5 5/10 44/92 2/18 16/32 1/15n/N=
n/a
![Page 34: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/34.jpg)
Relapse Rates by IL28B Genotype and
Prior Response
Patients with viral relapse (%)
Prior relapsers
Prior partial
responders
Prior null responders
CC CT TT CC CT TT CC CT TT
Pooled T12/PR48 (n=209)Pbo/PR48 (n=52)
Pooled T12/PR48 (n=79)Pbo/PR48 (n=20)
Pooled T12/PR48 (n=134)Pbo/PR48 (n=33)
2/56 6/10 8/112 12/18 2/33 2/5 1/7 0/1 10/44 0/2 3/13 0/5 11/40 2/3 4/14 1/2n/N=
Relapse was defined as having confirmed detectable HCV RNA levels during the entire follow-up period (relapse Week 72)
n/an/a
![Page 35: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/35.jpg)
IL28b C allele use is even less clear beyond boceprevir and
telaprevir
• May play a role with IFN sparing DAA o HCV protease may inhibit and its inhibition
may have larger effect with C allele• More potent regimens will mask the
IL28b difference
![Page 36: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/36.jpg)
More potent HCV regimens will overwhelm IL28b C allele
advantage
Pilar investigators Aerssens EASL 2011
![Page 37: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/37.jpg)
Clinical Applications of IL28b Testing in HCV genotype 1
infection• IL28b testing provides information that
is useful for estimating treatment response but not generally necessary for care of HCV infected persons
• IL28b genotype discriminates less as treatment potency improves and will someday be unhelpful
![Page 38: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/38.jpg)
Clinical Applications of IL28b Testing in HCV genotype 1
infection• Timing of treatment of acute infection
o Start sooner for unfavorable genotype• Timing of treatment for chronic
infection o Delay for unfavorable genotype and low
disease stage• Not to withhold HCV protease inhibitor• Staging (CC noninvasive to detect
cirrhosis)• Transplant: ?? IL28b favorable liver for
IL28b unfavorable recipient
![Page 39: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/39.jpg)
![Page 40: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/40.jpg)
SNPs on chromosome 20 strongly associated with Hb
decline at week 4• Hemoglobin change at week 4 of
PegIFN/RBV: > 3 g/dL and < 10 g/dL
• Anemia occurred in 9.1 – 11% of the population
• Among European Americans – rs6051702 had genome wide significance; P = 10-45
o Weaker among African and Hispanic Americans
• Inosine triphosphatase (ITPA) gene o 2 gene mutation cause ITPA
deficiency
![Page 41: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/41.jpg)
Predicted ITPA deficiency is associated with less Hb decline at treatment week 4
![Page 42: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/42.jpg)
Population Frequency of ITPA deficiency
![Page 43: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/43.jpg)
Protective mechanism of ITPA deficiency is not known but does not
impact SVR• RBV metabolism
differs in nucleated and non-nucleated cells
• RBV-TP accumulates → deplete ATP → hemolysis
• Potential mechanism(s)o Accumulation of
ITP modifies the ratio of RBV-TP and ATP
↓ Inosine-MP↓
phosphate
Page T; Connor JD. Int J Biochem; 1990;22:379; Homma et al Clin Gastro Hepatol 2004;2:337; Bierau J et al. Future medicine 2007;8:1221
![Page 44: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/44.jpg)
SNP at ribavirin transporter gene influences SVR post pegIFN and
ribavirin
Morello JID 2010
![Page 45: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/45.jpg)
Clinical application of ITPA testing
• Not commercially available in USA• Might inform RBV dose• Might inform patient counseling• Might inform timing of rEPO
![Page 46: Using genetic markers in clinical practice David Thomas Advisor: Merck Clinical trial: Gilead and Merck](https://reader036.vdocuments.us/reader036/viewer/2022062511/5514cf9a550346935c8b4d9d/html5/thumbnails/46.jpg)
Personalized Medicine for Hepatitis C
• IL28b gives important information on likelihood of spontaneous clearance and SVR
• Future applications of ITPA and other discoveries are changing